Method of treating migraines and pharmaceutical compositions

ABSTRACT

A combination of a 5HT 1B/1D  agonist and a COX-2 selective inhibitor is useful in the treatment and or prevention of migraine.

BACKGROUND OF THE INVENTION

Migraines are recurrent, often familial, symptom complexes of periodicattacks of vascular headache. Migraines affect approximately 17% ofadult women and 6% of adult men (Stewart et al., Neurology, 1994, 44(suppl. 4), 517-523). It has been known for some time that sumatriptan,which causes constriction of cranial blood vessels, is an effectivetreatment for migraine (see, for example, Doenicke et al., Lancet, 1988,Vol. 1, 1309-11; and Feniuk & Humphrey, Drug Development Research, 1992,26, 235-40). As such, it is the prototypical example of a class ofcompounds, including rizatriptan, which have recently been classified(Hartig et al., TIPS, 1996, 17, 103-105) as 5-HT_(1B/1D) receptoragonists.

Activation of 5-HT_(1B) and/or 5-HT_(1D) receptors leads to (1)selective vasoconstriction of certain cranial extracerebral blood vesselsegments; (2) pre-junctional inhibition of the release ofproinflammatory neuropeptides from sensory nerve terminals in themeninges; and (3) attenuation of central nociceptive neurotransmissionby inhibition of neurotransmitter release within the trigeminal nucleuscaudalis. It is believed that one or more of these three mechanisms isinvolved in the anti-migraine action of 5-HT_(1B/1D) receptor agonistssuch as rizatriptan.

Cyclooxygenase (COX), also known as prostaglandin H synthase, is anenzyme implicated in the mediation of pain, fever and inflammation. Itcatalyzes the oxidative conversion of arachidonic acid intoprostaglandin H₂, a key intermediate in the biosynthetic pathway ofprostaglandins, prostacyclins and thromboxanes, which in turn mediate avariety of physiological effects both beneficial and pathological.Recently it was discovered that two COX isoforms exist: COX-1, expressedconstitutively in many tissues, and COX-2, an induced isoform havingelevated levels of expression in inflamed tissues. COX-1 is thought tobe involved in ongoing “housekeeping” functions, for example, gastriccytoprotection, while COX-2 is implicated in the pathological effectsmentioned above.

Current cyclooxygenase inhibitors such as aspirin, ibuprofen andindomethacin, used as non-steroidal anti-inflammatory drugs (NSAIDs),inhibit both COX-1 and COX-2 and have associated side effects, such asgastrotoxicity, which may be manifested as ulcer formation. COX-2selective inhibitors act as effective NSAIDs without substantialgastrotoxic side effects. For purposes of this disclosure only, a COX-2selective inhibitor is defined as a COX inhibitor having a selectivityfor the COX-2 isoform relative to the COX-1 isoform.

The treatment of migraines by coadministration of a 5HT agonist and atraditional analgesic, including a NSAID has been described ininternational patent application WO98/06392.

It has now been found that migraines can be more effectively treatedand/or controlled by the co-administration of a 5-HT_(1B/1D) receptoragonist in combination with a COX-2 selective inhibitor, than with a5HT_(1B/1D) agonist alone, and more safely than with a traditionalanalgesic in combination with a 5HT agonist.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating or preventingmigraines in a mammalian patient in need thereof, which comprisesadministering to said patient an anti-migraine effective amount of acombination of a COX-2 selective inhibitor and a 5-HT_(1B/1D) receptoragonist.

The invention also relates to a pharmaceutical composition comprising aCOX-2 selective inhibitor, a 5-HT_(1B/1D) receptor agonist and apharmaceutically acceptable carrier therefore.

DETAILED DESCRIPTION

One embodiment of the present invention is a method of treating orpreventing migraine with an anti-migraine effective amount of acombination of a 5HT_(1B/1D) agonist and a COX-2 selective inhibitor.Another embodiment of the invention is a pharmaceutical compositioncomprising a combination of a 5HT_(1B/1D) agonist and a COX-2 selectiveinhibitor and a pharmaceutically acceptable carrier.

In these two embodiments, examples of the 5HT_(1B/1D) agonist can beselected from rizatriptan (EP 0,497,512), sumatriptan (GB 2,162,522),naratriptan (GB 2,208,646), zolmitriptan (WO91/18897), eleptriptan(WO92/06973), and almotriptan (WO94/02460).

The preferred 5HT_(1B/1D) agonist for use in this invention isrizatriptan, which isN,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine,the benzoate salt thereof being particularly preferred.

Examples of COX-2 inhibitors useful in the methods and compositionsdescribed herein include Celebrex® (celecoxib), VIOXX®, MK-663(WO98/03484), compounds disclosed in WO07/14691, meloxicam, RS 57067,valdecoxib (U.S. Pat. No. 5,663,272) and a compound of the structure:

In the novel method of treatment described herein, the two activeingredients can be administered combined in a single dosage form such asdescribed as one embodiment of this invention, or as two separate dosageforms, each containing one of the active ingredients, the two beingadministered substantially concurrently.

In one aspect of the invention, a method of treating or preventingmigraine is disclosed in a mammalian patient in need of such treatment,which comprises administering to the patient a COX-2 selectiveinhibiting compound and a 5HT_(1B/1D) agonist, or salts or hydratesthereof, in amounts that are effective for treating or preventingmigraines.

More particularly, a method is disclosed wherein the 5HT_(1B/1D) agonistis selected from the group consisting of: sumitriptan, naratriptan,zolmitriptan, eleptriptan, almatriptan and rizatriptan and the COX-2selective inhibiting compound is selected from the group consisting of:meloxicam,2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine(MK-663), VIOL® (valdecoxib), RS 57067, Celebrex® (celecoxib), and acompound of structure:

Even more particularly, a methodis disclosed wherein the COX-2 selectiveinhibitor is VIOXX® and the 5HT_(1B/1D) agonist is rizatriptan or a saltor hydrate thereof.

In one aspect, the method is described wherein the 5HT_(1B/1D) agonistand COX-2 inhibitor are administered combined in a single dosage form.

In another aspect, the method is described wherein the 5HT_(1B/1D)agonist and COX-2 inhibitor are administered as separate dosage formssubstantially concurrently.

In a different aspect, a pharmaceutical composition is included hereinwhich is comprised of a 5HT_(1B/1D) agonist and a COX-2 selectiveinhibiting compound, or salts or hydrates thereof, in combination with apharmaceutically acceptable carrier.

More particularly, the composition is described wherein the 5HT_(1B/1D)agonist is selected from sumitriptan, naratriptan, zolmitriptan,eleptriptan, almatriptan and rizatriptan, and the COX-2 inhibitor isselected from MK-663, VIOXX®, meloxicam, RS57067, celoxib, valdecoxiband a compound of structure:

Even more particularly, the composition is described wherein the5HT_(1B/1D) agonist is rizatriptan or a salt thereof, and the COX-2inhibitor is VIOXX®.

In a preferred combination, a composition is described whereinrizatriptan or a salt thereof, is present in an amount ranging fromabout 1 to about 10 mg, and VIOXX® is present in an amount ranging fromabout 10 mg to about 100 mg. More particularly, the rizatriptan ispresent as the benzoate salt, and VIOXX.

An anti-migraine effective amount of the combination is that amount thatwill relieve the subject being treated of the symptoms of the migraineattack and the specific dose level and frequency of dosage may vary andwill depend upon a variety of factors including the activity of thespecific compounds used in combination, the metabolic stability andlength of action of the compounds, the age, body weight, general health,sex diet, mode and time of administration, rate of excretion, theseverity of the particular condition and the host undergoing therapy.However, dosage levels of the 5HT_(1B/1D) on the order of about 0.001mg/kg to about 250 mg/kg of body weight per day, typically about 0.005to about 100 mg/kg, more particularly about 0.01 to about 50 mg/kg andespecially about 0.05 to about 10 mg/kg per day are useful in the novelmethod of treatment. Dosage levels of the COX-2 inhibitor of about 0.1to 500 mg/kg of body weight per day, typically about 0.5 to about 250mg/kg, more particularly about 5 to about 100 mg/kg and especially about10 to about 50 mg/kg of body weight per day are useful in the novelmethod of this invention.

For the treatment of a migraine attack, the active ingredients,separately or in combination, may be administered orally, topically,parenterally, by inhalation, spray, rectally or intravaginally informulations containing pharmaceutically acceptable carriers.

The term parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasisternal injection or infusiontechniques.

The separate-active agents or the novel composition of this inventionmay be in a form suitable for oral use, for example, tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, solutions, syrups and elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and typically such compositions contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preservatives in order to providepharmaceutically elegant and palatable preparations. These excipientsmay be for example, diluents such as lactose, calcium carbonate, sodiumcarbonate, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch or alginic acid; bindingagents, for example starch, gelatin or acacia, and lubricating agents,for example, magnesium stearate, stearic acid or talc.

The tablets may be uncoated or they may be coated. Coating can beincluded to delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed. They may also be coated by the techniquedescribed in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 toform osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The individual agents or the pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions. The oilyphase may be a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. Suitableemulsifying agents may be naturally-occurring phosphatides, for examplesoy bean, lecithin, and esters or partial esters derived from fattyacids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxy-ethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain demulcents, preservatives, flavourants and colouringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.

Injectable compositions are typically in the form of sterile solutionsor suspensions, which include the active ingredient in aparenterally-acceptable diluent. Among these are sterile water, dextrose5% in water (D5W), Ringer's solution and isotonic saline, as well asmixtures thereof. Cosolvents such as ethanol, propylene glycol orpolyethylene glycols may also be used. Sterile, injectable oil isoccasionally employed as a solvent or suspending medium in intramuscularpreparations. A representative example is peanut oil. In addition, fattyacids such as oleic acid, preservatives, buffers and local anestheticsfind use in the preparation of intramuscular injectables.

The combination of active ingredients may also be administered rectallyor intravaginally as suppositories. These can be prepared by mixing thedrug with a suitable non-irritating excipient which is solid at ordinaryroom temperature but molten at normal or elevated body temperature.Examples of such materials include cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, gels, solutions, suspensions and thelike containing the compound are employed.

(For purposes of this application, topical application includes mouthwashes and gargles, as well as transdermal applications.) Topicalformulations are comprised of a pharmaceutical carrier, which mayinclude, e.g., cosolvents, emulsifiers, penetration enhancers,preservatives or emollients.

The active ingredients are combined with the carrier to produce thedosage form. For example, a formulation intended for oral administrationmay contain from as low as about 0.1 mg of the novel combination to ashigh as about 5 g of combination per dose, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition.

EXAMPLES 1 AND 2

Tablet Preparation

Tablets containing 5 mg and 10 mg of rizatriptan benzoate and 10 mg ofVioxx were prepared as follows: Example 1 Example 2 Rizatriptan benzoate 5.0 mg 10.0 mg Vioxx 10.0 mg 10.0 mg Microcrystalline cellulose 42.0 mg39.5 mg Modified food corn starch 42.0 mg 39.5 mg Magnesium stearate 1.0 mg  1.0 mg

All of the active ingredients, cellulose, and a portion of the cornstarch are mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and magnesium stearate. The resulting granulation is thencompressed into tablets.

1. A method of treating migraine in a mammalian patient in need of suchtreatment, which comprises administering to the patient a COX-2selective inhibiting compound and a 5HT_(1B/1D) agonist, or salts orhydrates thereof, in amounts that are effective for treating migraines.2. The method according to claim 1 wherein the 5HT_(1B/1D) agonist isselected from the group consisting of: sumitriptan, naratriptan,zolmitriptan, eletriptan, almotriptan and rizatriptan and the COX-2selective inhibiting compound is selected from the group consisting of:meloxicam, MK-663, VIOXX®, RS 57067, celecoxib, valdecoxib and acompound of structure:


3. The method according to claim 2 wherein the COX-2 selective inhibitoris VIOXX® and the 5HT_(1B/1D) agonist is rizatriptan.
 4. The method ofclaim 1 wherein the 5HT_(1B/1D) agonist and COX-2 inhibitor areadministered combined in a single dosage form.
 5. The method of claim 1wherein the 5HT_(1B/1D) agonist and COX-2 inhibitor are administered asseparate dosage forms substantially concurrently. 6-10. (canceled) 11.The method according to claim 4 wherein the single dosage formcomprises: 5 mg of rizatriptan benzoate, 10 mg of VIOXX®, 42 mg ofmicrocrystalline cellulose, 42 mg of modified food corn starch and 1 mgof magnesium stearate or 10 mg of rizatriptan benzoate, 10 mg of VIOXX®,39.5 mg of microcrystalline cellulose, 39.5 mg of modified food cornstarch and 1 mg of magnesium stearate.
 12. The method according to claim1 wherein the COX-2 selective inhibiting compound is VIOXX®.
 13. Themethod according to claim 1 wherein the COX-2 selective inhibitingcompound is MK-663.
 14. The method according to claim 13 wherein the5HT_(1B/1D) agonist is rizatriptan or a salt thereof.
 15. The methodaccording to claim 1 wherein the COX-2 selective inhibiting compound iscelecoxib.
 16. The method according to claim 1 wherein the COX-2selective inhibiting compound is valdecoxib.
 17. The method according toclaim 1 wherein the COX-2 selective inhibitor is celecoxib and the5HT_(1B/1D) agonist is eletriptan or a salt thereof.